CA1200508A - Method for inhibiting mineralization of natural tissue during implantation - Google Patents
Method for inhibiting mineralization of natural tissue during implantationInfo
- Publication number
- CA1200508A CA1200508A CA000435133A CA435133A CA1200508A CA 1200508 A CA1200508 A CA 1200508A CA 000435133 A CA000435133 A CA 000435133A CA 435133 A CA435133 A CA 435133A CA 1200508 A CA1200508 A CA 1200508A
- Authority
- CA
- Canada
- Prior art keywords
- solution
- weight
- tissue
- sodium
- phosphate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
- A61L27/3683—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
- A61L27/3687—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/02—Treatment of implants to prevent calcification or mineralisation in vivo
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/915—Method or apparatus for preparing biological material
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
- Y10S623/915—Method or apparatus for preparing biological material
- Y10S623/916—Blood vessel
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Botany (AREA)
- Dermatology (AREA)
- General Chemical & Material Sciences (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Transplantation (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Materials For Medical Uses (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Prostheses (AREA)
Abstract
ABSTRACT
Natural tissues fixed with a tanning solution such as glutaraldehyde and intended for implantation in humans, e.g., porcine heart valve prosthetic devices, are treated with a solution of a water soluble phosphate ester such as sodium dodecyl hydrogen phosphate to inhibit mineraliza-tion, particularly calcification, of the tissue after implantation.
Natural tissues fixed with a tanning solution such as glutaraldehyde and intended for implantation in humans, e.g., porcine heart valve prosthetic devices, are treated with a solution of a water soluble phosphate ester such as sodium dodecyl hydrogen phosphate to inhibit mineraliza-tion, particularly calcification, of the tissue after implantation.
Description
METHOD FOR INHIBITING MINERALIZATION OF NATURAL TISSUE
DURING IMPLANTATION
BACKGROUND OF INVE~TION
This invention relates to the preparation of natural tissue for implantation, and more particularly, to the treatment of fixed tissue to inhibit mineralization, particularly calcification, u~on i~plantation.
Animal tissues have in recent years found wide acceptance in the preparation of various prosthetic devices for use in humans. Most notable of these is the use of porcine heart valves to replace defective mitral, tricuspid and aortic valves in humans. Also of interest is the preparation of arteries, veins and hu~an u~bilical cords for use as arterial grafts and other tubular duct replacement in humans.
Porcine heart valves have been in use for several years with generally good results. The preparation of such valves for implantation is described in the literature and in the patent art as, for example, in U.S. Patents Nos.
3,~66,401 and 4,050,893. Briefly, the valve is excised from the donor heart, trimmed and cleaned, and fixed by iml~ersion in a tanning fluid such as a 0.2% glutaraldehyde solution. After several hours oE treatment, the fixed valve is removed from the glutara~dehyde, rinsed, mounted on a stent, and stored in a glutaraldehyde solution until ready for use.
One problem which has been associated with the porcine heart valve in some individuals is calcification of the valve leaflets after an extçnded period of time resulting in reduced flexibility and eventual loss of efficienCy in the operation of t~le valve. Significant calcification is readily visible in an Y~-ray of the affected valve.
ECP 7~
3,~
U.S. 4,323,358 discloses a method for inhibiting mineralization, particularly calcification, of fixed natural tissue by treat~ent with a salt of a sulfated higher aliphatic alcohol such as sodium dodecyl sulfate.
It is an object of the present invention to provide another method to inhibit mineralization, and particularly calcification, of fixed natural tissue upon implantation.
It is a fur'her object of this invention to provide a method for treatment of fixed porcine heart valve tissue to inhibit minerali~ation when used as a prosthetic valve replacement in humans.
These and other objects of the present invention will be apparent from the ensuing description and claims.
As used herein, the term "fixed" or "fixed tissue" refers to tissue which has been treated with a tanning solution such as ~% formaldehyde or 0.2% glutaraldehyde ~or a period of time and under conditions conventionally used to prepare natural tissue for implantation. The tanning process does not form any part of the present invention.
SUMMAR~ OF INVENTION
Natural tissue such as porcine heart valves which have been fixed for implantation in accordance with conven-tional procedures are treated prior to implantation with a solution of a water soluble phosphate ester having the o formula RlO-P-OR2, wherein at least one of R1, R~ and R3 is an alkyl group con~aining from 7 to 15 carbon atoms.
An example of a water soluble phosphate ester which may be ~Z~05~
used in the practice of the invention is sodium dodecyl hydrogen phosphate (SDHP).
The treatment may be effected in a 1% sol~ltion of SDHP in distilled water or an aqueous electrolyte solution at ambient temperatures and for a period of 7 days. The treated tissue is removed from the SDHP solution, rinsed, and returned to storage in sterile glutaraldehyde until needed for implantation.
lG
DESCRIPTION OF PREFERRED EMBODIMENTS
In the method of the present invention, fixed natural tissue is treated with an aqueous solution of a water O
soluble phosphate ester having the formula RlO-~-OR2, wherein at least one of R 1~ R2 and R3 is an alkyl group containing from 7 to 15 carbons. In the preferred water soluble phosphate esters, R~ is an alkyl group containing 7 to 15 carbons, R2 is hydrogen and R3 is selected from the group consisting of sodium, potassium, ammonium and organic amine. The preferred water soluble phosphate esters include the water soluble salts of monodecyl hydrogen phosphate, monododecyl hydrogen phosphate and monomyristyl hydrogen phosphate. Most preferably, the water soluble phosphate ester is sodium dodecyl hydrogen phosphate (SDHP); that is, in the most preferred water soluble phosphate ester, Rl is a 12-carbon alkyl group, R~
is hydrogen and R3 is sodium. The alkyl unit may be straight chain or branched and mixtures of two or more phosphate esters may be used if`the mixture is soluble-in aqueous solution. The phosphate ester is preferably soluble in water at room temperature to a concentration of a least 2~, and preferably at least about 5%, by weight.
In the preferred embodiment, the phosphate ester is EC~-7~
dissolved in an aqueous electrolyte solution comprising up to about 1~ by weight of sodium chloride, up to about 0.05~ by weight each of potassium chloride, magnesium sulfate heptahydrate and dipotassium hydrogen phosphate, and up to about 0.1% by weight of sodium dihydrogen phosphate. As indicated above, sodium dodecyl hydrogen phosphate (SDHP) is most particularly preferred and its use is illustrated in the following detailed example. The ln formula of SDHP is (CI2H~5O)P(OH)O~a; its molecular weight is 288.3.
An SDHP treatment solution (1~ w/v) was prepared by dis-solving 10 9O of SDHP in a sufficient quantity of an aqueous electrolyte solution (AES) to bring the total volume of treatment solution to 1 liter. Aqueous electro-lyte solution (AES) is an aqueous solution containing approximately 0.8~ by weight of sodium chloride, 0.04~ by weight of potassium chloride, 0.02% by weight of magnesium sulfate heptahydrate, 0.02% by weight of dipotassium hydrogen phosphate and 0.0~% sodium dihydrogen phosphate.
The pH of the AES is adjusted to 7.35 - 7.45 with either
DURING IMPLANTATION
BACKGROUND OF INVE~TION
This invention relates to the preparation of natural tissue for implantation, and more particularly, to the treatment of fixed tissue to inhibit mineralization, particularly calcification, u~on i~plantation.
Animal tissues have in recent years found wide acceptance in the preparation of various prosthetic devices for use in humans. Most notable of these is the use of porcine heart valves to replace defective mitral, tricuspid and aortic valves in humans. Also of interest is the preparation of arteries, veins and hu~an u~bilical cords for use as arterial grafts and other tubular duct replacement in humans.
Porcine heart valves have been in use for several years with generally good results. The preparation of such valves for implantation is described in the literature and in the patent art as, for example, in U.S. Patents Nos.
3,~66,401 and 4,050,893. Briefly, the valve is excised from the donor heart, trimmed and cleaned, and fixed by iml~ersion in a tanning fluid such as a 0.2% glutaraldehyde solution. After several hours oE treatment, the fixed valve is removed from the glutara~dehyde, rinsed, mounted on a stent, and stored in a glutaraldehyde solution until ready for use.
One problem which has been associated with the porcine heart valve in some individuals is calcification of the valve leaflets after an extçnded period of time resulting in reduced flexibility and eventual loss of efficienCy in the operation of t~le valve. Significant calcification is readily visible in an Y~-ray of the affected valve.
ECP 7~
3,~
U.S. 4,323,358 discloses a method for inhibiting mineralization, particularly calcification, of fixed natural tissue by treat~ent with a salt of a sulfated higher aliphatic alcohol such as sodium dodecyl sulfate.
It is an object of the present invention to provide another method to inhibit mineralization, and particularly calcification, of fixed natural tissue upon implantation.
It is a fur'her object of this invention to provide a method for treatment of fixed porcine heart valve tissue to inhibit minerali~ation when used as a prosthetic valve replacement in humans.
These and other objects of the present invention will be apparent from the ensuing description and claims.
As used herein, the term "fixed" or "fixed tissue" refers to tissue which has been treated with a tanning solution such as ~% formaldehyde or 0.2% glutaraldehyde ~or a period of time and under conditions conventionally used to prepare natural tissue for implantation. The tanning process does not form any part of the present invention.
SUMMAR~ OF INVENTION
Natural tissue such as porcine heart valves which have been fixed for implantation in accordance with conven-tional procedures are treated prior to implantation with a solution of a water soluble phosphate ester having the o formula RlO-P-OR2, wherein at least one of R1, R~ and R3 is an alkyl group con~aining from 7 to 15 carbon atoms.
An example of a water soluble phosphate ester which may be ~Z~05~
used in the practice of the invention is sodium dodecyl hydrogen phosphate (SDHP).
The treatment may be effected in a 1% sol~ltion of SDHP in distilled water or an aqueous electrolyte solution at ambient temperatures and for a period of 7 days. The treated tissue is removed from the SDHP solution, rinsed, and returned to storage in sterile glutaraldehyde until needed for implantation.
lG
DESCRIPTION OF PREFERRED EMBODIMENTS
In the method of the present invention, fixed natural tissue is treated with an aqueous solution of a water O
soluble phosphate ester having the formula RlO-~-OR2, wherein at least one of R 1~ R2 and R3 is an alkyl group containing from 7 to 15 carbons. In the preferred water soluble phosphate esters, R~ is an alkyl group containing 7 to 15 carbons, R2 is hydrogen and R3 is selected from the group consisting of sodium, potassium, ammonium and organic amine. The preferred water soluble phosphate esters include the water soluble salts of monodecyl hydrogen phosphate, monododecyl hydrogen phosphate and monomyristyl hydrogen phosphate. Most preferably, the water soluble phosphate ester is sodium dodecyl hydrogen phosphate (SDHP); that is, in the most preferred water soluble phosphate ester, Rl is a 12-carbon alkyl group, R~
is hydrogen and R3 is sodium. The alkyl unit may be straight chain or branched and mixtures of two or more phosphate esters may be used if`the mixture is soluble-in aqueous solution. The phosphate ester is preferably soluble in water at room temperature to a concentration of a least 2~, and preferably at least about 5%, by weight.
In the preferred embodiment, the phosphate ester is EC~-7~
dissolved in an aqueous electrolyte solution comprising up to about 1~ by weight of sodium chloride, up to about 0.05~ by weight each of potassium chloride, magnesium sulfate heptahydrate and dipotassium hydrogen phosphate, and up to about 0.1% by weight of sodium dihydrogen phosphate. As indicated above, sodium dodecyl hydrogen phosphate (SDHP) is most particularly preferred and its use is illustrated in the following detailed example. The ln formula of SDHP is (CI2H~5O)P(OH)O~a; its molecular weight is 288.3.
An SDHP treatment solution (1~ w/v) was prepared by dis-solving 10 9O of SDHP in a sufficient quantity of an aqueous electrolyte solution (AES) to bring the total volume of treatment solution to 1 liter. Aqueous electro-lyte solution (AES) is an aqueous solution containing approximately 0.8~ by weight of sodium chloride, 0.04~ by weight of potassium chloride, 0.02% by weight of magnesium sulfate heptahydrate, 0.02% by weight of dipotassium hydrogen phosphate and 0.0~% sodium dihydrogen phosphate.
The pH of the AES is adjusted to 7.35 - 7.45 with either
2~ sodium hydroxide or 2N hydrochloric acid prior to use.
The pH of the SDHP treatment solution was 3Ø
Fifty pieces of fixed porcine valve cusp tissue weighing from about 20 to 30 mg. each were rinsed in AES to remove tlle glutaraldehyde, then placed in 50 ml. of the SDIIP
treatment solution at an ambient temperature of 20-25C
for 7 days.
After completion of the SDHP treatment, the tissue pieces were rinsed in 0.2~ glutaraldehyde solution and stored in 0.2~ glutaraldehyde solution. Subsequently, the tissue pieces were sterilized for 24 hours in an aqueous solution containing 1% glutaraldehyde and 20~ isopropyl alcohol, and stored in sterile 0.2~ glutaraldehyde solution to await implarltation.
ECP-7~
The effectiveness of the SDHP treatment in retarding cal-cification of the fixed tissue was determined by animal implant studies according to the following procedure.
Male Sprague-Dawley rats weighing 180-200 g. were anesthe-tized and prepared for abdominal surgery under sterile conditions. The abdominal area was shaved and disinfec-ted, and a lengthwise midline skin incision approximately a cmO long was made in the ventral surface. The skin was separated from the underlying muscle, and three small pouches were for~ed in the muscle on either side of the midline incision by a small incision followed by blunt dissection of the abdominal muscle wall. One piece of SDHP-treated tissue, rinsed in sterile saline to remove the glutaraldehyde, was inserted in each muscle pouch.
The skin incision was closed and the animal returned to its cage. Implantations were made in 5 rats for a total of 30 pieces of SDHP-treated tissue. A control group of 5 rats were implanted under identical conditions with a total of 30 pieces of fixed porcine valve cusp tissue not subjected to the SDHP treatment.
The rats from both the control group and the SDHP test group were sacrificed after twelve weeks and the implanted tissue examined for calcification by X-ray and by analysis for Ca+~ levels. The entire abdominal muscle with implants in situ was excised and X-rayed. The implanted specimens were then removed and two set aside for histological examination. The remaining four implants were dissected free of surrounding tissue and extracted individually in 5 ml. of 0.6 N HCl at 70C for 96 hours.
The extract solution was then assayed for calcium ion by atomic absorption spectrophotometry. Prior experience had established that, where tissue is analyzed and found to contain Ca+2 levels of less than 1 ~g. per mg. of wet tissue, all of the Ca+~ so found is attributable to normal ECP-7~
~2~Q~
physiological processes and none is attributable to a process of mineralization. In other words, it can be concluded that no mineralization has occurred in tissue whose Ca+2 levels are found to be less than 1 ~g. per mg.
of wet tissue.
The results of the animal study are presented in Table I.
TABLE I
DEGREE OF CALCIFICATION
SDHP - Treated Porcine Cusp Tissue Rat No. X-Ray (2) Extraction ~1) Histology ~3) 15 1 0/6 0.25 ~ 0.02 0/l*
2 0/6 0.26 + 0.03 0/2
The pH of the SDHP treatment solution was 3Ø
Fifty pieces of fixed porcine valve cusp tissue weighing from about 20 to 30 mg. each were rinsed in AES to remove tlle glutaraldehyde, then placed in 50 ml. of the SDIIP
treatment solution at an ambient temperature of 20-25C
for 7 days.
After completion of the SDHP treatment, the tissue pieces were rinsed in 0.2~ glutaraldehyde solution and stored in 0.2~ glutaraldehyde solution. Subsequently, the tissue pieces were sterilized for 24 hours in an aqueous solution containing 1% glutaraldehyde and 20~ isopropyl alcohol, and stored in sterile 0.2~ glutaraldehyde solution to await implarltation.
ECP-7~
The effectiveness of the SDHP treatment in retarding cal-cification of the fixed tissue was determined by animal implant studies according to the following procedure.
Male Sprague-Dawley rats weighing 180-200 g. were anesthe-tized and prepared for abdominal surgery under sterile conditions. The abdominal area was shaved and disinfec-ted, and a lengthwise midline skin incision approximately a cmO long was made in the ventral surface. The skin was separated from the underlying muscle, and three small pouches were for~ed in the muscle on either side of the midline incision by a small incision followed by blunt dissection of the abdominal muscle wall. One piece of SDHP-treated tissue, rinsed in sterile saline to remove the glutaraldehyde, was inserted in each muscle pouch.
The skin incision was closed and the animal returned to its cage. Implantations were made in 5 rats for a total of 30 pieces of SDHP-treated tissue. A control group of 5 rats were implanted under identical conditions with a total of 30 pieces of fixed porcine valve cusp tissue not subjected to the SDHP treatment.
The rats from both the control group and the SDHP test group were sacrificed after twelve weeks and the implanted tissue examined for calcification by X-ray and by analysis for Ca+~ levels. The entire abdominal muscle with implants in situ was excised and X-rayed. The implanted specimens were then removed and two set aside for histological examination. The remaining four implants were dissected free of surrounding tissue and extracted individually in 5 ml. of 0.6 N HCl at 70C for 96 hours.
The extract solution was then assayed for calcium ion by atomic absorption spectrophotometry. Prior experience had established that, where tissue is analyzed and found to contain Ca+2 levels of less than 1 ~g. per mg. of wet tissue, all of the Ca+~ so found is attributable to normal ECP-7~
~2~Q~
physiological processes and none is attributable to a process of mineralization. In other words, it can be concluded that no mineralization has occurred in tissue whose Ca+2 levels are found to be less than 1 ~g. per mg.
of wet tissue.
The results of the animal study are presented in Table I.
TABLE I
DEGREE OF CALCIFICATION
SDHP - Treated Porcine Cusp Tissue Rat No. X-Ray (2) Extraction ~1) Histology ~3) 15 1 0/6 0.25 ~ 0.02 0/l*
2 0/6 0.26 + 0.03 0/2
3 0/6 0.27 + 0.03 0/2
4 0/6 0.28 + 0.02 0/2 0/6 0.28 ~ 0.03 0/1*
Controls: Non-SDHP-Treated Porcine Cusp Tissue Rat NoO X-Ray (2) Extraction (l) Histology (3) 1 4/6 4.02 + 4.81 2/2 2 4/6 8.07 + 6.4% 2/2 25 3 3/6 4.2~ + 7.19 2/2 4 3/6 2.29 + 3.3 2/2 2/6 2.51 + 2.15 1/1*
(1) Average of 4 values, ~g Ca~~+/mg wet wt. tissue (2) Evaluated by visual examination; 4/6 = 4 of 6 samples evidenced a significant degree of calcification.
(3) Evaluated by visual examination of stained samples;
2/2 = 2 samples evidenced a significant degree of calcification.
* = Second sample was not recovered
Controls: Non-SDHP-Treated Porcine Cusp Tissue Rat NoO X-Ray (2) Extraction (l) Histology (3) 1 4/6 4.02 + 4.81 2/2 2 4/6 8.07 + 6.4% 2/2 25 3 3/6 4.2~ + 7.19 2/2 4 3/6 2.29 + 3.3 2/2 2/6 2.51 + 2.15 1/1*
(1) Average of 4 values, ~g Ca~~+/mg wet wt. tissue (2) Evaluated by visual examination; 4/6 = 4 of 6 samples evidenced a significant degree of calcification.
(3) Evaluated by visual examination of stained samples;
2/2 = 2 samples evidenced a significant degree of calcification.
* = Second sample was not recovered
5~t~
Three eontrol samples of abdominal muscle tissue were taken from each of the rats at the same time the abdominal muscle eontaining the implanted SDHP-treated and non-SDHP-treated poreine eusp tissue samples was exeised from the saerificed animals. These eontrol samples were taken from a location in the muscle away from the site of the implanted poreine eusp tissue. The Ca+2 levels in the abdominal musele eontrol samples were determined by the atomie absorption spectrophotometric method described above. The Ca~ 2 level in the abdominal muscle eontrol samples is indieative of the amount of Ca+2 whieh one would expeet to find in the implanted poreine eusp tissue as a result of its exposure to the host's normal physiologieal processes and without the oceurrence of any mineralization.
The average Ca+2 level in the abdominal musele eontrol samples of the rats in whose abdominal muscle the SDHP-treated porcine cusp tissue had been implanted was 20 0.08 + 0.07 micrograms per milligram (~g. per mg.) of wet tissue (overall average of 3 determinations on each of 5 rats). The average Ca+2 level in the explanted SDHP-treated porcine cusp tissue whieh had been implanted in the abdominal musele was 0.27 + 0.02 ~g. per mg. wet tissue (overall average of 4 determinations on each of 5 rats). It was concluded ~rom this data that no mineralization had occurred in the SDHP-treated cusp tissue. This conelusion is consistent with and supported by the X-ray and histology results set forth under the heading "SDHP-Treated Porcine Cusp Tissue" in Table I.
ECP-7~
The average Ca+2 level in the abdominal muscle control samples taken from the control rats (i.e., those rats in whose abdominal muscle the non-5DHP-treated porcine CU5p tissue had been implanted) was 0.48 ~ 0.13 ~g. per mg. wet tissue (overall average of 3 determinations on each of 5 rats). The average Ca+2 level in the explanted non-SDHP-treated porcine cusp tissue which had been implanted in the abdominal muscle of the control rats was 4.22 + 5.0~ ~9. per mg. wet tissue. It was concluded from this data that a significant degree of mineralization had occurred in the non-SDHP-treated cusp tissue. This conclusion is consistent with and supported by the X-ray and histology results set forth under the heading "Controls: Non-SDHP-Treated Porcine Cusp Tissue" in Table I.
As illustrated by the data in Table I, the SDHP treat~ent was effective to substantially inhibit calcification of the porcine valve cusp tissue for a period of 12 weeks under the severe calcification conditions inherent in the rat test. The correlation between calcification in the rat test and human experience is such that the extensive calcification detected in the rat control group after 12 weeks would not be expected to occur in humans until after several years exposure. The SDHP treatment woul~
accordingly be expected to retard calcification in humans for an additional period of years beyond that normally experienced prior to the onset of calcification.
The procedure described above is one that has produced good results and constitutes a preferred embodiment of the present invention. The scope of the present invention, however, is not to be limited by the details of the des-cribed procedure, and it will be apparent to those skilled in the art that many variations in this procedure are possible. For example, the concentration of the SDHP
ECP-7~
~2~ 8 _9_ treatment solution may range from about 0.1 to 5.0~ or higher, and other water soluble phosphate esters or salts of.phosphate esters may be substituted for the SDHP.
Treatment temperatures may range from about 5C to 50C;
and treatment times may vary from as little as 1 day to as much as 4 weeks.
The pH of the treatment solution may range from about 2.0 to about 10.0 and will depend on the chemical structur~ of the water soluble phosphate est-r and the presence of desired buffering agents as well as the composition of the aqueous electrolyte solution if such is used instead of distilled water in preparing the phosphate ester treatment solution. In addition, other ingredients both active and inactive may be utiliæed in combination with the phosphate ester in the treatment solution. Such variations may be developed by those skilled in the art with little or no experimentation to suit individual desires.
While the preceding example has also been limited to the treatment of porcine heart valve cusp tissue, the inven-tion is equally applicable to the treatment of veins, arteries, and other tissues taken from pigs, other animals, or humans, all of which are known to be useful for implantation in humans. Human umbilical cords, for example, have been used as arterial grafts after fixation in glutaraldehyde. Similarly, porcine and bovine arteries and veins have also been suggested for use as arterial grafts and A-V fistula grafts. All such tissues are suitable for use in the practice of the present invention.
ECP-7~
Three eontrol samples of abdominal muscle tissue were taken from each of the rats at the same time the abdominal muscle eontaining the implanted SDHP-treated and non-SDHP-treated poreine eusp tissue samples was exeised from the saerificed animals. These eontrol samples were taken from a location in the muscle away from the site of the implanted poreine eusp tissue. The Ca+2 levels in the abdominal musele eontrol samples were determined by the atomie absorption spectrophotometric method described above. The Ca~ 2 level in the abdominal muscle eontrol samples is indieative of the amount of Ca+2 whieh one would expeet to find in the implanted poreine eusp tissue as a result of its exposure to the host's normal physiologieal processes and without the oceurrence of any mineralization.
The average Ca+2 level in the abdominal musele eontrol samples of the rats in whose abdominal muscle the SDHP-treated porcine cusp tissue had been implanted was 20 0.08 + 0.07 micrograms per milligram (~g. per mg.) of wet tissue (overall average of 3 determinations on each of 5 rats). The average Ca+2 level in the explanted SDHP-treated porcine cusp tissue whieh had been implanted in the abdominal musele was 0.27 + 0.02 ~g. per mg. wet tissue (overall average of 4 determinations on each of 5 rats). It was concluded ~rom this data that no mineralization had occurred in the SDHP-treated cusp tissue. This conelusion is consistent with and supported by the X-ray and histology results set forth under the heading "SDHP-Treated Porcine Cusp Tissue" in Table I.
ECP-7~
The average Ca+2 level in the abdominal muscle control samples taken from the control rats (i.e., those rats in whose abdominal muscle the non-5DHP-treated porcine CU5p tissue had been implanted) was 0.48 ~ 0.13 ~g. per mg. wet tissue (overall average of 3 determinations on each of 5 rats). The average Ca+2 level in the explanted non-SDHP-treated porcine cusp tissue which had been implanted in the abdominal muscle of the control rats was 4.22 + 5.0~ ~9. per mg. wet tissue. It was concluded from this data that a significant degree of mineralization had occurred in the non-SDHP-treated cusp tissue. This conclusion is consistent with and supported by the X-ray and histology results set forth under the heading "Controls: Non-SDHP-Treated Porcine Cusp Tissue" in Table I.
As illustrated by the data in Table I, the SDHP treat~ent was effective to substantially inhibit calcification of the porcine valve cusp tissue for a period of 12 weeks under the severe calcification conditions inherent in the rat test. The correlation between calcification in the rat test and human experience is such that the extensive calcification detected in the rat control group after 12 weeks would not be expected to occur in humans until after several years exposure. The SDHP treatment woul~
accordingly be expected to retard calcification in humans for an additional period of years beyond that normally experienced prior to the onset of calcification.
The procedure described above is one that has produced good results and constitutes a preferred embodiment of the present invention. The scope of the present invention, however, is not to be limited by the details of the des-cribed procedure, and it will be apparent to those skilled in the art that many variations in this procedure are possible. For example, the concentration of the SDHP
ECP-7~
~2~ 8 _9_ treatment solution may range from about 0.1 to 5.0~ or higher, and other water soluble phosphate esters or salts of.phosphate esters may be substituted for the SDHP.
Treatment temperatures may range from about 5C to 50C;
and treatment times may vary from as little as 1 day to as much as 4 weeks.
The pH of the treatment solution may range from about 2.0 to about 10.0 and will depend on the chemical structur~ of the water soluble phosphate est-r and the presence of desired buffering agents as well as the composition of the aqueous electrolyte solution if such is used instead of distilled water in preparing the phosphate ester treatment solution. In addition, other ingredients both active and inactive may be utiliæed in combination with the phosphate ester in the treatment solution. Such variations may be developed by those skilled in the art with little or no experimentation to suit individual desires.
While the preceding example has also been limited to the treatment of porcine heart valve cusp tissue, the inven-tion is equally applicable to the treatment of veins, arteries, and other tissues taken from pigs, other animals, or humans, all of which are known to be useful for implantation in humans. Human umbilical cords, for example, have been used as arterial grafts after fixation in glutaraldehyde. Similarly, porcine and bovine arteries and veins have also been suggested for use as arterial grafts and A-V fistula grafts. All such tissues are suitable for use in the practice of the present invention.
ECP-7~
Claims (26)
1.. A method for inhibiting the mineralization of fixed natural tissue after implantation in a living body comprising contacting fixed natural tissue intended for implantation with an aqueous solution of a water soluble phosphate ester having the formula wherein at least one of R1, R2 and R3 is an alkyl group having from 7 to 15 carbon atoms.
2. The method of Claim 1 wherein the pH of the aqueous solution ranges from about 2 to about 10.
3. The method of Claim 1 wherein said phosphate ester is a monoalkyl ester and said alkyl group is selected from the group consisting of decyl, dodecyl and myristyl.
4. The method of Claim 1 wherein the alkyl group is a straight chain aliphatic group.
5. The method of Claim 1 wherein the alkyl group is a branched aliphatic group.
6. The method of Claim 1 wherein R1 is an alkyl group having from 7 to 15 carbons, R2 is hydrogen, and R3 is selected from the group consisting of sodium, potassium, ammonium and organic amine.
7. The method of Claim 6 wherein said alkyl group is selected from the group consisting of decyl, dodecyl and myristyl.
8. The method of Claim 6 wherein said alkyl group is a dodecyl group.
9. The method of Claim 1 wherein said natural tissue is contacted with said solution for a time sufficient to effectively inhibit future calcification of said tissue after implant.
10. The method of Claim 1 wherein said natural tissue is contacted with said solution for a period of at least 24 hours at ambient temperature.
11. The method of Claim 1 wherein the concentration of said phosphate ester in said solution is from about 0.1 to 5% by weight.
12. The method of Claim 11 wherein the solution has a pH
of from about 2 to about 10.
of from about 2 to about 10.
13. The method of Claim 11 wherein said solution com-prises, in addition to said phosphate ester, up to about 1% by weight of sodium chloride, up to about 0.05% by weight each of potassium chloride, magnesium sulfate heptahydrate and dipotassium hydrogen phosphate, and up to about 0.1% by weight of sodium dihydrogen phosphate.
14. The method of Claim 11 wherein said solution com-prises, in addition to said phosphate ester, about 0.8% by weight of sodium chloride, about 0.04% by weight of potas-sium chloride, about 0.02% by weight each of magnesium sulfate heptahydrate and dipotassium hydrogen phosphate, and about 0.08% by weight of sodium dihydrogen phosphate.
15. The method of Claim 14 wherein the pH of said solution is about 3.
16. A method for inhibiting the calcification of fixed natural tissue after implantation in a living body which comprises contacting fixed tissue intended for implanta-tion with a solution comprising sodium dodecyl hydrogen phosphate for a time sufficient to effectively inhibit future calcification of said tissue after implantation.
17. The method of Claim 16 wherein said solution comprises from about 0.1 to 5% by weight sodium dodecyl hydrogen phosphate.
18. The method of Claim 16 wherein said tissue is contacted with said solution for a time of at least about 7 days.
19. The method of Claim 16 wherein the pH of said solution ranges from about 2 to about 10.
20. The method of Claim 19 wherein the concentration of sodium dodecyl hydrogen phosphate is about 1%.
21. The method of Claim 19 wherein the tissue is contacted with said solution of sodium dodecyl hydrogen phosphate for a period of about 7 days at ambient temperature.
22. The method of Claim 16 wherein said solution includes, in addition to sodium dodecyl hydrogen phos-phate, up to about 1% by weight of sodium chloride, up to about 0.05% by weight each of potassium chloride, magnesium sulfate heptahydrate and dipotassium hydrogen phosphate, and up to about 0.1% by weight of sodium dihydrogen phosphate.
23. The method of Claim 16 wherein said solution includes, in addition to sodium dodecyl hydrogen phos-phate, about 0.8% by weight sodium chloride, about 0.04%
potassium chloride, about 0.02% by weight each of magne-sium sulfate heptahydrate and dipotassium hydrogen phosphate, and about 0.08% by weight of sodium dihydrogen phosphate.
potassium chloride, about 0.02% by weight each of magne-sium sulfate heptahydrate and dipotassium hydrogen phosphate, and about 0.08% by weight of sodium dihydrogen phosphate.
24. The method of Claim 23 wherein the pH of said solution is about 3.
25. The method of Claim 16 wherein the fixed tissue is a glutaraldehyde-fixed porcine heart valve.
26. The method of Claim 16 wherein said living body is a human.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/411,191 US4402697A (en) | 1982-08-25 | 1982-08-25 | Method for inhibiting mineralization of natural tissue during implantation |
| US411,191 | 1982-08-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1200508A true CA1200508A (en) | 1986-02-11 |
Family
ID=23627950
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000435133A Expired CA1200508A (en) | 1982-08-25 | 1983-08-23 | Method for inhibiting mineralization of natural tissue during implantation |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4402697A (en) |
| EP (1) | EP0103947A3 (en) |
| JP (1) | JPS5937944A (en) |
| BR (1) | BR8303581A (en) |
| CA (1) | CA1200508A (en) |
| ES (1) | ES525137A0 (en) |
| ZA (1) | ZA836277B (en) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5215541A (en) * | 1982-11-12 | 1993-06-01 | Baxter International Inc. | Surfactant treatment of implantable biological tissue to inhibit calcification |
| US4885005A (en) * | 1982-11-12 | 1989-12-05 | Baxter International Inc. | Surfactant treatment of implantable biological tissue to inhibit calcification |
| WO1984001879A1 (en) * | 1982-11-12 | 1984-05-24 | American Hospital Supply Corp | Surfactant treatment of implantable biological tissue to inhibit calcification |
| EP0147431A4 (en) * | 1983-05-24 | 1987-04-15 | American Hospital Supply Corp | Protective device for implantable prosthesis. |
| US4894063A (en) * | 1983-05-24 | 1990-01-16 | Baxter International Inc. | Barrier layer for implantable tendons and ligaments |
| US4753652A (en) * | 1984-05-04 | 1988-06-28 | Children's Medical Center Corporation | Biomaterial implants which resist calcification |
| US4553974A (en) * | 1984-08-14 | 1985-11-19 | Mayo Foundation | Treatment of collagenous tissue with glutaraldehyde and aminodiphosphonate calcification inhibitor |
| US4597766A (en) * | 1984-10-26 | 1986-07-01 | American Hospital Supply Corporation | Implantable bioprosthetic tendons and ligaments |
| US4770665A (en) * | 1985-11-05 | 1988-09-13 | American Hospital Supply Corporation | Elastomeric polymer incorporation into implantable biological tissue to inhibit calcification |
| US4729139A (en) * | 1985-11-05 | 1988-03-08 | Baxter Travenol | Selective incorporation of a polymer into implantable biological tissue to inhibit calcification |
| IL83592A0 (en) * | 1986-08-20 | 1988-01-31 | Childrens Medical Center | Biomaterial implant |
| US4786287A (en) * | 1986-10-10 | 1988-11-22 | Baxter Travenol Laboratories | Process for decreasing residual aldehyde levels in implantable bioprosthetic tissue |
| US4800603A (en) * | 1987-01-30 | 1989-01-31 | Jaffe Norman R | Tissue fixation with vapor |
| JP2529112B2 (en) * | 1987-08-31 | 1996-08-28 | 株式会社 高研 | Biological valve |
| US5746775A (en) * | 1988-04-01 | 1998-05-05 | The Board Of Regent6S Of The University Of Michigan | Method of making calcification-resistant bioprosthetic tissue |
| CA2046592C (en) * | 1989-02-17 | 2000-05-02 | Aws Nashef | Calcification mitigation of bioprosthetic implants |
| US5192312A (en) * | 1991-03-05 | 1993-03-09 | Colorado State University Research Foundation | Treated tissue for implantation and methods of treatment and use |
| US5476516A (en) * | 1992-03-13 | 1995-12-19 | Albert Einstein College Of Medicine Of Yeshiva University | Anticalcification treatment for aldehyde-tanned biological tissue |
| US5437287A (en) * | 1992-08-17 | 1995-08-01 | Carbomedics, Inc. | Sterilization of tissue implants using iodine |
| US5509932A (en) * | 1993-04-08 | 1996-04-23 | Keogh; James R. | Fixed tissue medical devices comprising albumin-binding dyes |
| KR100365573B1 (en) * | 1994-03-14 | 2004-08-25 | 크라이어라이프, 인크. | Transplantation tissue and its manufacturing method |
| US5595571A (en) * | 1994-04-18 | 1997-01-21 | Hancock Jaffe Laboratories | Biological material pre-fixation treatment |
| DE69523074T2 (en) * | 1994-07-29 | 2002-06-06 | Edwards Lifesciences Corp | METHOD FOR TREATING IMPLANTABLE BIOLOGICAL TISSUES TO REDUCE CALCIFICATION |
| US5931969A (en) * | 1994-07-29 | 1999-08-03 | Baxter International Inc. | Methods and apparatuses for treating biological tissue to mitigate calcification |
| US6302909B1 (en) * | 1996-07-31 | 2001-10-16 | St. Jude Medical, Inc. | Calcification-resistant biomaterials |
| US5782931A (en) * | 1996-07-30 | 1998-07-21 | Baxter International Inc. | Methods for mitigating calcification and improving durability in glutaraldehyde-fixed bioprostheses and articles manufactured by such methods |
| US5891196A (en) * | 1997-04-16 | 1999-04-06 | Baxter International Inc. | Method for actively binding heparin to crosslinked biological tissues |
| US5862806A (en) * | 1997-10-30 | 1999-01-26 | Mitroflow International, Inc. | Borohydride reduction of biological tissues |
| US6394096B1 (en) | 1998-07-15 | 2002-05-28 | Corazon Technologies, Inc. | Method and apparatus for treatment of cardiovascular tissue mineralization |
| US6527979B2 (en) * | 1999-08-27 | 2003-03-04 | Corazon Technologies, Inc. | Catheter systems and methods for their use in the treatment of calcified vascular occlusions |
| US6214054B1 (en) | 1998-09-21 | 2001-04-10 | Edwards Lifesciences Corporation | Method for fixation of biological tissues having mitigated propensity for post-implantation calcification and thrombosis and bioprosthetic devices prepared thereby |
| US6524339B1 (en) | 1999-01-27 | 2003-02-25 | David H. Adams | Cryopreserved homografts and other stentless bioprosthetic heart valves having natural tissue sewing rings |
| US6471723B1 (en) | 2000-01-10 | 2002-10-29 | St. Jude Medical, Inc. | Biocompatible prosthetic tissue |
| US6878168B2 (en) | 2002-01-03 | 2005-04-12 | Edwards Lifesciences Corporation | Treatment of bioprosthetic tissues to mitigate post implantation calcification |
| US7579381B2 (en) * | 2005-03-25 | 2009-08-25 | Edwards Lifesciences Corporation | Treatment of bioprosthetic tissues to mitigate post implantation calcification |
| EP2077718B2 (en) | 2006-10-27 | 2022-03-09 | Edwards Lifesciences Corporation | Biological tissue for surgical implantation |
| US9101691B2 (en) | 2007-06-11 | 2015-08-11 | Edwards Lifesciences Corporation | Methods for pre-stressing and capping bioprosthetic tissue |
| US8357387B2 (en) | 2007-12-21 | 2013-01-22 | Edwards Lifesciences Corporation | Capping bioprosthetic tissue to reduce calcification |
| NZ602706A (en) | 2010-03-23 | 2014-02-28 | Edwards Lifesciences Corp | Methods of conditioning sheet bioprosthetic tissue |
| US8906601B2 (en) | 2010-06-17 | 2014-12-09 | Edwardss Lifesciences Corporation | Methods for stabilizing a bioprosthetic tissue by chemical modification of antigenic carbohydrates |
| US9351829B2 (en) | 2010-11-17 | 2016-05-31 | Edwards Lifesciences Corporation | Double cross-linkage process to enhance post-implantation bioprosthetic tissue durability |
| US10238771B2 (en) | 2012-11-08 | 2019-03-26 | Edwards Lifesciences Corporation | Methods for treating bioprosthetic tissue using a nucleophile/electrophile in a catalytic system |
| US9615922B2 (en) | 2013-09-30 | 2017-04-11 | Edwards Lifesciences Corporation | Method and apparatus for preparing a contoured biological tissue |
| US10959839B2 (en) | 2013-10-08 | 2021-03-30 | Edwards Lifesciences Corporation | Method for directing cellular migration patterns on a biological tissue |
| US11103619B2 (en) | 2018-08-30 | 2021-08-31 | Efstathios-Andreas AGATHOS | Anticalcification treatment for impantable biological tissues using calcitonin |
| EP3852683A1 (en) | 2018-11-01 | 2021-07-28 | Edwards Lifesciences Corporation | Transcatheter pulmonic regenerative valve |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3966401A (en) * | 1974-07-01 | 1976-06-29 | Hancock Laboratories Incorporated | Preparing natural tissue for implantation so as to provide improved flexibility |
| US4050893A (en) * | 1974-07-22 | 1977-09-27 | Hancock Laboratories, Inc. | Arrangement for preparing natural tissue for implantation |
| US4323358A (en) * | 1981-04-30 | 1982-04-06 | Vascor, Inc. | Method for inhibiting mineralization of natural tissue during implantation |
-
1982
- 1982-08-25 US US06/411,191 patent/US4402697A/en not_active Expired - Lifetime
-
1983
- 1983-06-20 JP JP58111749A patent/JPS5937944A/en active Pending
- 1983-07-04 EP EP83303881A patent/EP0103947A3/en not_active Ceased
- 1983-07-04 BR BR8303581A patent/BR8303581A/en unknown
- 1983-08-23 CA CA000435133A patent/CA1200508A/en not_active Expired
- 1983-08-24 ZA ZA836277A patent/ZA836277B/en unknown
- 1983-08-24 ES ES525137A patent/ES525137A0/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| BR8303581A (en) | 1984-04-24 |
| US4402697A (en) | 1983-09-06 |
| ES8506455A1 (en) | 1985-07-16 |
| ZA836277B (en) | 1985-04-24 |
| EP0103947A2 (en) | 1984-03-28 |
| ES525137A0 (en) | 1985-07-16 |
| JPS5937944A (en) | 1984-03-01 |
| EP0103947A3 (en) | 1985-03-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1200508A (en) | Method for inhibiting mineralization of natural tissue during implantation | |
| US4405327A (en) | Method for inhibiting mineralization of natural tissue during implantation | |
| US4323358A (en) | Method for inhibiting mineralization of natural tissue during implantation | |
| AU701897B2 (en) | Method of making calcification-resistant bioprosthetic tissue | |
| CA2312376C (en) | Method for inhibiting calcification of aldehyde-fixed bioprosthetic materials | |
| CA1221641A (en) | Implantable biological tissue and process for preparation thereof | |
| CA2884689C (en) | Method for the preparation of biological tissue for dry use in an implant | |
| EP0306256B1 (en) | Bioprosthetic valve | |
| Cartmell et al. | Development of cell-seeded patellar tendon allografts for anterior cruciate ligament reconstruction | |
| EP0065827B1 (en) | Calcification resistant tissue for implantation | |
| Tingfei et al. | Prevention of tissue calcification on bioprosthetic heart valve by using epoxy compounds: a study of calcification tests in vitro and in vivo | |
| WO1993019209A1 (en) | Anticalcification treatment for aldehyde-tanned biological tissue | |
| JPH10507102A (en) | Method for treating implantable biological tissue to reduce calcification and bioprostheses treated in such a manner | |
| AU692330B2 (en) | Method for reducing calcification of biological tissue used in implantable bioprostheses | |
| CN108535205A (en) | External biological valve anticalcium processing method, calcification evaluation method | |
| Levy et al. | Calcification of valved aortic allografts in rats: effects of age, crosslinking, and inhibitors | |
| VAN DE PUTTE et al. | Experimental mineralization of collagen sponge and decalcified bone | |
| CA1254839A (en) | Retarded mineralization of implantable tissue by surface active betaines | |
| Lentz et al. | Prevention of intrinsic calcification in porcine and bovine xenograft materials | |
| EP0277995A1 (en) | Biomaterial implant with a net positively charged surface | |
| JPH0159241B2 (en) | ||
| AU773150B2 (en) | A method using potassium dihydrogen phosphate to reduce calcification of tissue | |
| PL163828B1 (en) | Method of obtaining a preserved natural tissue for implantation | |
| WO2000074692A1 (en) | A method using potassium dihydrogen phosphate to reduce calcification of tissue |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |